Polymer systems are being developed for various in vivo applications, including delivery vehicles for controlled release of drugs when implanted in a subject's body. Such systems are particularly useful for therapeutic biomolecules such as proteins or peptides, which tend to be very sensitive to degradation within the body. Polymer systems can be designed that exhibit altered properties in response to changes in environment, such as changes in temperature, pH and surrounding solution conditions.
In particular, the synthesis of thermogelling polymers has attracted much attention because of their suitability for applications such as drug delivery and tissue engineering (1-6). Bioactive agents can be incorporated in the solution state at low temperatures, which can then be injected in vivo where the higher body temperature induces formation of a gel depot. This depot can be used for the controlled release of the bioactive agents. Biodegradability of the polymers is advantageous, since degradation of the polymer into smaller fragments allows for subsequent removal of the polymer from the body. Low critical gelation concentration (“CGC”) is also preferred, as lower concentrations of polymer can be used to create a gel, resulting in smaller amounts of polymer being implanted in a subject.
As an example of thermogelling polymers, Pluronics™ or Poloxamers™, the triblock copolymers of poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) (PEG-PPG-PEG), have been widely investigated for controlled drug delivery (6, 7), wound covering (8), and chemosensitizing for cancer therapy (9). However, these polymers generally have a high CGC, typically 15-20 wt % or above, exhibit poor resilience, and tend to exhibit burst effect in the release of bioactive agents. These shortcomings have made this system unsuitable for many biomedical applications (10-11). Moreover, Pluronics™ copolymers are non-biodegradable and have been reported to induce hyperlipidemia and increase the plasma level of cholesterol in rabbits and rats, suggesting that its use in the human body may not be an attractive option (12-14).
Attempts have been made to lower the CGCs of a thermogelling copolymer containing Pluronics™. By grafting Pluronic™ to poly(acrylic acid), polymers having very low CGCs (0.1 wt %) have been synthesized (15-18). However, these polymers are non-biodegradable and clearance from the body could be difficult.
High molecular weight multi-block Pluronics™ with a short junction linkages have been synthesized and found to exhibit lower CGCs than Pluronics™ (19-20).
Cohn et al. have synthesized reverse thermogelling multi-block copolymers based on PEG, PPG and oligo-caprolactone (21). These biodegradable copolymers exhibited CGCs of 10 wt %; the incorporation of oligo-caprolactone segments lowered the CGCs of the copolymers as compared with the PPG/PEG multi-block copolymers. The viscosities of the gels were also lowered compared with the PPG/PEG multiblock copolymers.
Pluronic™ analogs were developed where the middle PPG block was replaced by a biodegradable polyester such as poly(ε-caprolactone) or poly(L-lactide). Although the CGCs of such polymers occur in a similar range compared to Pluronics™ (22), these polymers are more useful in biomedical applications because of their biodegradability.
Thus, there exists a need for a biodegradable, thermogelling polymer that exhibits a lower CGC compared to existing polymers such as Pluronics™.